The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells.
The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells.
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DOI：
10.1038/s41467-023-39733-6
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发表时间：
2023-07-05
影响因子：
16.6
通讯作者：
Lieberman AP
中科院分区：
文献类型：
--
作者：
Kunkel TJ;Townsend A;Sullivan KA;Merlet J;Schuchman EH;Jacobson DA;Lieberman AP
细胞内胆固醇转运蛋白NPC 1在晚期内体和溶酶体中发挥功能，以排出未酯化的胆固醇，其缺乏导致C型尼曼-皮克病，这是一种常染色体隐性溶酶体疾病，其特征在于进行性神经变性和早期死亡。在这里，我们使用单核RNA-seq对P16的Npc 1 −/−小鼠前脑进行研究，以确定发病早期受影响的细胞类型和途径。我们的分析揭示了发育髓鞘形成过程中少突胶质细胞谱系的显着转录变化，同时伴有髓鞘形成少突胶质细胞成熟度的降低。我们发现在Npc 1 −/−少突胶质细胞系细胞中与神经发生和突触形成相关的基因上调，反映了H3 K27 me 3减少的基因沉默。Npc 1 −/−少突胶质细胞祖细胞在体外复制受损的成熟，这种表型可以通过GSK-J 4（一种H3 K27去甲基化酶的小分子抑制剂）治疗来挽救。此外，通过在P7单次给予2-羟丙基-β-环糊精动员Npc 1 −/−小鼠中储存的胆固醇，挽救了髓鞘形成、表观遗传标记和少突胶质细胞基因表达。我们的研究结果强调了NPC 1在少突胶质细胞谱系成熟和表观遗传调控中的重要作用，并确定了治疗干预的潜在靶点。C型尼曼-匹克病的特征在于内溶酶体胆固醇转运蛋白NPC 1的缺乏。在这里，作者在Npc 1 −/−小鼠中表明，NPC 1的缺失通过扰乱表观遗传调控损害了少突胶质细胞谱系细胞分化和发育髓鞘形成。
The intracellular cholesterol transporter NPC1 functions in late endosomes and lysosomes to efflux unesterified cholesterol, and its deficiency causes Niemann–Pick disease Type C, an autosomal recessive lysosomal disorder characterized by progressive neurodegeneration and early death. Here, we use single-nucleus RNA-seq on the forebrain of Npc1−/− mice at P16 to identify cell types and pathways affected early in pathogenesis. Our analysis uncovers significant transcriptional changes in the oligodendrocyte lineage during developmental myelination, accompanied by diminished maturation of myelinating oligodendrocytes. We identify upregulation of genes associated with neurogenesis and synapse formation in Npc1−/− oligodendrocyte lineage cells, reflecting diminished gene silencing by H3K27me3. Npc1−/− oligodendrocyte progenitor cells reproduce impaired maturation in vitro, and this phenotype is rescued by treatment with GSK-J4, a small molecule inhibitor of H3K27 demethylases. Moreover, mobilizing stored cholesterol in Npc1−/− mice by a single administration of 2-hydroxypropyl-β-cyclodextrin at P7 rescues myelination, epigenetic marks, and oligodendrocyte gene expression. Our findings highlight an important role for NPC1 in oligodendrocyte lineage maturation and epigenetic regulation, and identify potential targets for therapeutic intervention. Niemann-Pick type C disease is characterized by deficiency of the endolysosomal cholesterol transporter NPC1. Here, the authors show in Npc1−/− mice that loss of NPC1 impairs oligodendrocyte lineage cell differentiation and developmental myelination through perturbed epigenetic regulation.
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影响因子：
6.2
作者：
Figlia G;Gerber D;Suter U
通讯作者：
Suter U
DOI：
10.1523/jneurosci.6000-09.2010
发表时间：
2010-03-10
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
De Biase LM;Nishiyama A;Bergles DE
通讯作者：
Bergles DE
影响因子：
56.9
作者：
Ge, Woo-Ping;Yang, Xiu-Juan;Duan, Shumin
通讯作者：
Duan, Shumin
影响因子：
3.5
作者：
Elrick, Matthew J.;Yu, Ting;Lieberman, Andrew P.
通讯作者：
Lieberman, Andrew P.
影响因子：
2.7
作者：
CARSON, JH;NIELSON, ML;BARBARESE, E
通讯作者：
BARBARESE, E